title: Synthesis of peptidyl fluoromethyl ketones and peptidyl alpha-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G.
abstract: Comparison of MeO-Suc-Val-Pro-Phe-CO2Me (29) and MeO-Suc-Ala-Ala-Pro-Phe- CO2Me (25) with their corresponding trifluoromethyl ketones 9a and 9b, respectively, in rat and human neutrophil cathepsin G assays showed the alpha-keto esters to be more potent inhibitors. Likewise, Ac-Pro-Ala-Pro-Ala-CO2Me (21) was more potent than its corresponding trifluoromethyl ketone (9c) in both porcine pancreatic elastase and human neutrophil elastase assays. Within a set of Ala-Ala-Pro-Val-CF3 elastase inhibitors, the carbobenzyloxy (Cbz) N-protecting group conferred greater potency as a P5 site recognition unit for elastase than did dansyl, methoxysuccinyl, or tert-butyloxycarbonyl. Initial inhibition of elastase was greater when trifluoromethyl ketone 9f was added from a stock solution of dimethyl sulfoxide than when it had been buffer-equilibrated prior to assay, which suggests that the nonhydrated ketone is the more effective form of the inhibitor. The most potent elastase inhibitor we report is Na-(Ad-SO2)-N epsilon-(MeO-Suc)Lys-Pro-Val-CF3 (16) which has a Ki of 0.58 nM.
authors.affiliation: Merrell Dow Research Institute, Cincinnati, Ohio 45215.
authors.forename: N P
authors.initials: NP
authors.lastname: Peet
authors.forename: J P
authors.initials: JP
authors.lastname: Burkhart
authors.forename: M R
authors.initials: MR
authors.lastname: Angelastro
authors.forename: E L
authors.initials: EL
authors.lastname: Giroux
authors.forename: S
authors.initials: S
authors.lastname: Mehdi
authors.forename: P
authors.initials: P
authors.lastname: Bey
authors.forename: M
authors.initials: M
authors.lastname: Kolb
authors.forename: B
authors.initials: B
authors.lastname: Neises
authors.forename: D
authors.initials: D
authors.lastname: Schirlin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010179:Pancreas / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors; D051381:Rats; D012697:Serine Endopeptidases; D013237:Stereoisomerism; D013552:Swine
chemical_list: D007659:Ketones; D009842:Oligopeptides; D011480:Protease Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase